Cyclopentanophenanthrene derivatives and process



pllit id tates Patent O ,2,888,470\I:"" CYCLOPENTANOPHENANTHRENE DERIVATIYES ANDPROCESS Howard J. Ringold, Franz Sondheimer, and George Rosenkranz, Mexico City, Mexico, assignors to Syntex S.A., Mexico City, Mexico, a corporation of Mexico No Drawing. Application 'August 13, 1954 Serial No. 449,766

Claimspriority,

4 Claims. 01. 260.. 397.4)

The present invention relates to a novel process for the production of cyclopentanophenanthrene compounds and to certain novel cyclopentanophenanthrene compounds and intermediates.

More particularly, thepresent invention relates to a novel method for the production of esters of the androgenic hormone testosterone and dihydrotestosterone, a novel method for the production ofthe cortical hormone l 7"-hydroxy progesterone and to a novel method for the production of a new-cortical hormone A -preglnadien-3,20 dione-2l-ol and its esters. a "In our United States Patencappli'cation Serial No. 401,058, filed December 29, 1953, now Patent No. 2,802,- 839, there is disclosed a novel process for the production of steroidal 3-ketones from the corresponding steroidal 3-formates involving the treatment of the 3-formateswith an aluminum alkoxide in the presence of a hydrogen.

acceptor.

In accordance with the present invention it has been discovered that this oxidation treatment of 3-formates producing corresponding steroidal 3-ketones forms in combination with certain other steps a novel process for the production of esters of testosterone from the known application Mexico August 18, 1953 n no starting material dehydroepiandrosterone (A -androstene, 3fi-ol-l7-one), as well as for the production of dihy-' drotestosterone and/or its esters from the known start-j ing material androsten-3fi-ol-17-one. It has further been discovered in accordance with the present inventionthat sodium borohydride in solution in an organic solvent,

preferably an organic ether solvent, is capable of reducfl ing keto groups to hydroxyl groups even in the presence of other esterified groups, and that in particular it is not capable of even saponifyin-g the formate group which tion ofthe 3-formate-17-acy1ate and finally, the selective oxidation of the 3-formate by means ofan aluminum alkoxide in the presence of a hydrogen acceptor. There further been discovered infaccordance with the present invention a novel cortical hormone A -pregnadien-3,20-dione-21-ol and its esters as well as thepreparation of this novel hormone by treatment of the ,Q formate-ZI-acylate of A -pr egnadiene-3}8,2l-diol 2Q- one with an aluminum alkoxide in the presence of a hyf span. a r

Patented May 26, 1959 ice A portion of the process of the present invention is exemplifiedby the following equation: I

y l5 niosg fi Sodium borohydride ether solvent acid agent Aluminum alkoxide hydrogen acceptor esterification residue of a lower fatty acid or an aromatic acid such as benzoic acid. The character of R, of course, depends on the particular acylating agent utilized for the third step of the above set-forth reaction.

In general, in practicing the reaction above set-forth dehydroisoandrosterone is dissolved in formic acid and the solution kept for a period of time of the order of one hour at an elevated temperature, as for example C. The reaction solution is then cooled and poured into water to precipitate the formate of dehydroisoandrosterone, which is suitably purified as by crystallization solvents suchas mixtures of acetone-hexane. For the second step of the above equation the formate of dehydroisoandrosterone is dissolved in an organic ether solvent. This organic ether solvent may be anhydrous or it may contain a small percentage of H O,-'as for example ,of

the order of one percent and such solvents are referred to hereinafter as substantially anhydrous. Suitable ,solvents' for this'purpose are for example tetrahydrofurane or dioxan. The sodium borohydride is preferably dissolved in the solvent prior to the addition of the .formate. The reaction mixture of solvent, sodium borohydride and formate is then stirred for a substantial period ofitime, as of therorder' of three hours, at room temperature and then formic acid is added to destroy the excess of sodiumborohydride. Upon concentratiomprecipitation water, and purification the corresponding assae'zo 3 3-f0rmate of A -androstene-3fi,l7fl-diol is obtained. The 3-formate of A -androstene-3 3,l7B-diol is then treated with an acylating agent as for example acetic anhydride or propionic anhydride in the presence of p-toluenesulpregnene-lip,17u-diol-20-one. This 3-formate-17-acetate is then dissolved in an inert organic solvent such as xylene containing cyclohexanone and aluminum isopropylate is then added thereto. As may be understood,

phonic acid preferably under mild conditions for a rela- 5 other inert solvents and ketone hydrogen acceptors as tively long period of time. There is thus produced the well as other aluminum alkoxides may be utilized. The corresponding 3-formate-l7-acylate of A -androsteneresultant compound is the l7-lower fatty acid acylate of 35,17p-diol. This compound is then dissolved in an inert the cortical hormone A -pregnene-l7a-ol-3,2O-dione. This solvent such as xylene or toluene and then treated with compound can then be saponified as for example with the usual type of aluminum alkoxides customarily used 10 dilute methanolic potassium hydroxide to give the corfor vOppenauer steroid oxidations, as for example, alumiresponding 17-alcohol M-pregnene-l7ot-ol-3,20-dione (17- nurn isopropylate in the presence of a hydrogen acceptor, hydroxy progesterone). preferably a ketone such as cyclohexanonc. Preferably, The following equation illustrates still another portion for this oxidation reaction the mixture was refluxed for a of the present invention:

CHgOR; OHQOR Aluminum 0 l alkoxide I H dr H' g O a cei t r short period of time such as 45 minutes. The organic In the above equation R represents the residue of a solvents are then removed and the precipitate when purisuitable acid customarily used for the esterification of fied was the corresponding ester of testosterone. 3o steroid hormones, preferably a lower fatty acid such as In exactly similar reaction to that just described startacetic or propionic or the residue of an aromatic acid ing with the corresponding saturated compound ansuch as benzoic. In accordance with the above equation drostan-Elp-ol-l7-0ne gave the corresponding ester of ana mixed ester such as the 3-formate-2l-acetate of A drostan-l7B-o1-3-0ne (ester of dihydrostestosterone). pregnadiene-3B-2l-diol-20-one, prepared in accordance The following equationillustrates another portion of the with United States application Serial No. 435,084, filed present invention: June 7, 1954, now Patent No. 2,791,593, is treated with CH; CH;

O 430 l---0H --0R1 Lower fatty acid 0 acylating agent 0 l H 0 Strong acid 1 Aluminum alkoxide lhydrogeu acceptor OH; to ,--OR:

In the above equation R represents the residue of a an aluminum alkoxide in the presence of a hydrogen aclower fatty acid produced 1n accordance with the-above ceptor in an inert solvent in accordance with the oxidaequation by the action of the lower fatty acid acylatlng tion steps previously described. The resultant compound agent. is a new cortical hormone l6-dehydro-desoxycorticos- In practicing the process above outlined the 3-formate tel-one, of A -pregnene-3 B,l7u-d1ol-2O-one prepared in accord- The following specific examples serve to illustrate but ance with our United States patent application Serial No. are not intended to limit the present invention:

401,058, is treated with a lower fatty acid anhydride in E l I the presence of a strong acid such as a halogen acid or xamp 8 strong organic acid as for example p-toluene sulfonic acid. 5 g. of dehydroisoandrosterone was dissolved in 55 cc. The mixture is preferably agitated for a relatively'long of formic acid and the solution was kept for one hour period as for example 9 hours at room temperature. at a temperature of 60 C. It was cooled, poured into There is thus produced the 3-formate-l7-acetate of A water and the precipitate was filtered, washed to neutral and dried. There was obtained 4.8 g. of the formate of dehydroisoandrosterone, which after crystallization from acetone-hexane gave the analytical sample with melting point 141-145 C. [al -8 (chloroform).

4 g. of the formate was dissolved in 150 cc. of distilled tetrahydrofurane and mixed with 1.5 cc. of water and 0.2 g.' of sodium borohydride. The mixture was stirred for 3 hours at room temperature and then formic acid was added to destroy the excess of hydride. The solution was concentrated, precipitated with water and the precipitate was filtered, washed and dried. 2.9 g. was obtained of the 3-formate of A -androstene-3B,l7i3-diol.

0.5 g. of the 3-formate of A -androstene-3fi,17}3-diol was oxidized by the method described in detail in Example 11, and after crystallization of the product from acetone-hexane, there was obtained 270 mg. of A -androstene- 3,17-dione with melting point 167-170 C.

Example ll 1 g. of the 3-formate of A -androstene-3B,17fi-diol and 0.34 g. of p-toluenesulphonic acid was dissolved in cc. of acetic anhydride and the mixture was kept for 16 hours at room temperature. The S-formate 17-acetate crystallized directly from the reaction mixture and was filtered, washed with water and dried. There was obtained 530 mg. with melting point 144148 C.; precipitation with water of the mother liquors atforded an additional 530 mg. with lower melting point and with a purity of approximately 50%.

0.5 g. of the 3-formate 17-acetate of M-androstene- 3fi,171S-diol was dissolved in cc. of xylene, mixed with 5 cc. of cyclohexanone and 3 cc. of the solution was distilled in order to remove traces of moisture. 0.5 g. of aluminum isopropylate was then added and the mixture was refluxed for 45 minutes, cooled and diluted with water; the organic solvents were removed by steam distillation, the residue was cooled and the precipitate was filtered and dried. Recrystallization from acetone-hexane yielded 250 mg. of the acetate of testosterone with melting point 137-140 C.

Example 111 Following the method described in Example H, except that propionic anhydride was used instead of acetic anhydride, there was obtained the 3-formate l7-propionate of A -androstene-3/3,l7p-diol, with melting point 106- 109 C. in 80% yield; [ad -65 (chloroform). Starting from this compound, the propionate of testosterone was obtained in 63% yield, with melting point 118- 121 C.

' Example IV 5 g. of the S-formate of A -pregnene-3B,l7a-diol-20-one prepared in accordance with out United States application Serial No. 401,058, suspended in 120 cc. of acetic anhydride was treated with 1.5 g. of p-toluenesulphonic acid and the mixture was stirred for 9 hours at room temperature. It was poured into water and after 2 hours standing, the precipitate was filtered and washed to neutral, thus yielding the 3-formate 17-acetate of A -pregnene-3p,17adiol--one in a yield of over 90%.

1 g. of this 3-formate 17-acetate was dissolved in 30 cc. of xylene and 10 cc. of cyclohexanone and 4 cc. of the solution were distilled in order to remove traces of moisture. 1 g. of aluminum isopropylate was added to the hot solution and the mixture was refluxed for 45 minutes. After cooling to 90 C., water was added and the organic solvents were removed by steam distillation. Salt was added to the aqueous suspension and the residue was filtered, dried and extracted with hot acetone. The acetone solution was evaporated to dryness and the residue was crystallized from chloroform-methanol, thus giving 610 mg. of the 17-acetate of A -pregnen-l7a-ol-3,20-dione (l7-acetoxy-progesterone) with melting point 239240 C. Saponification of this compound with 1% methanohc potassium hydroxide yielded 80% of A -pregnen 17a-ol- 3,20-dio'ne. Example V alumina. The crystalline fractions eluted from the column with benzene were combined and recrystallized from acetone-hexane, thus afiording 4.3 g. of the acetate of 16- dehydro-desoxycorticosterone with melting point 3 148 C. The analytical sample had melting point 152- 154 C, [:11 (chloroform), ultraviolet absorption maximum: A max. 240 my. (log E 4.44).

Example VI 7 g. of the 3-formate 2l-acetate of A -pregnadiene- 3fl,21-diol-20-one dissolved in 350 cc. of toluene and 120 cc. of cyclohexanone was subjected to the treatment in accordance with the method described in Example V. The acetate of 16-dehydro-desoxycorticosterone was obtained with the same yield and with the same characteristics as reported in Example V.

Example VII 10 g. of androstan-3fi-ol-l7-one was suspended in 250 cc. of 85% formic acid and the mixture was stirred for 2 hours at a temperature of 65 C. The cooled solution was poured into water, the precipitate was filtered, washed to neutral and dried. Recrystallization from acetonehexane yielded 8.9 g. of the formate of androstan-3p-ol- 17-one.

8 g. of the formate was dissolved in 300 cc. of distilled tetrahydrofurane and mixed with 3 cc. of water and 0.4 g. of sodium borohydride. The mixture was stirred for 3 hours at room temperature and then formic acid was added to destroy the excess of hydride. The solution was concentrated, precipitated with water and the precipitate was filtered, washed and dried. 5.8 g. was obtained of the 3-formate of androstane-3/3,17fi-diol.

5 g. of the 3-monoformate dissolved in 50 cc. of acetic anhydride was mixed with 1.5 g. of p-toluenesulphonic acid and kept overnight at room temperature. The 3- formate 17-acetate of androstane-3/3,17 8-diol crystallized directly from the reaction mixture. Filtration and purification by routine methods afforded 3.8 g. of the compound.

0.5 g. of the 3-formate l7-acetate of androstane-3p, 17/8-diol was dissolved in 15 cc. of xylene and 5 cc. of cyclohexanone and 3 cc. of the solution was distilled in order to remove traces of moisture. 0.5 g. of aluminum isopropylate was added and the mixture was refluxed for 45 minutes and cooled. The organic solvents were removed by steam distillation and the residue was extracted with chloroform, washed and evaporated to dryness. Recrystallization from acetone-hexane yielded 295 mg. of the 17-acetate of androstan-l7B-ol-3-one (acetate of dihydrotestosterone) with melting point 156-158 C.

We claim:

1. A method for the production of a'lower fatty acid ester of M-pregnene-l7a-ol-3,20-dione which comprises treating the 3-formate of A -pregnene-3fi,l7u-diol-20-one with a lower fatty acid acylating agent in the presence of a strong acid to form the corresponding 3-formate 17-lower fatty acid acylate and treating the last mentioned compound with an aluminum alkoxide in the a References Cited in the file of this patent UNITED STATES PATENTS Ehrhart May 15, 1-956 FOREIGN PATENTS Switzerland Ian. 16, 1941 Great Britain May 2 1 19 41 

1. A METHOD FOR THE PRODUCTION OF A LOWER FATTY ACID ESTER OF $4-PREGNENTE-17A-OL-3,20-DIONE WHICH COMPRISES TREATING THE 3-FORMATE OF $5-PREGNENE-3B,17A-DIOL-20-ONE WITH A LOWER FATTY ACID ACYLATING AGENT IN THE PRESENCE OF A STRONG ACID TO FORM THE CORRESPONDING 3-FORMATE 17-LOWER FATTY ACID ACYLATE AND TREATING THE LAST MENTIONED COMPOUND WITH AN ALUMINUM ALKOXIDE IN THE PRESENCE OF A KETONE HYDROGEN ACCEPTOR TO FORM THE LOWER FATTY ACID OF $4-PREGNENE-17A-OL-3,20-DIONE.
 3. A 3-FORMATE 17-LOWER FATTY ACYLATE OF $5 PREGNENE3B, 17A-DIOL-20-ONE. 